Acne is the most common skin disease affecting young people. In addition to psychological distress and feelings of low self-esteem, acne can lead to permanent facial scarring. The production of sebum (oil) by sebaceous glands is a key factor in the development of acne. Apart from isotretinoin and hormonal therapy, there are no drugs that effectively reduce sebum production. Unfortunately, these drugs have significant side effects, including birth defects. No recent advances have been made in our ability to therapeutically reduce sebum production in part due to our lack of knowledge regarding the mechanisms regulating human sebum production. The overall goal of this research is to elucidate the mechanisms that regulate human sebum production in order to identify novel therapeutic target sites whose pharmacological ligands will offer safe and effective alternatives to isotretinoin for the treatment of acne. Peroxisome proliferator-activated receptors (PPARs) and sterol response element binding proteins (SREBPs) are key transcriptional regulators of lipid metabolism in a variety of tissues. The central hypothesis to be tested is that PPARs regulate lipid metabolism in human sebaceous glands. The effects of linoleic acid and other PPAR agonists on lipid metabolism will be determined using assays of lipid transport, synthesis, and catabolism in addition to an analysis of gene expression. 13-cis retinoic acid is the most potent sebosuppressive agent. PPARs and retinoids share common DNA binding sites, and in this regard can mediate transcription of common genes. Our secondary hypothesis is that 13-cis retinoic acid reduces sebum production by altering the expression of PPAR-regulated genes. The effects of 13-cis retinoic acid on gene expression will be examined in human sebocytes and in skin from patients treated with isotretinoin. Data generated from the proposed experiments will advance our understanding of the mechanisms regulating sebum production and can lead to identification of potential additional therapeutic target sites in the treatment of acne.